This is the second competing renewal of our Program Project Grant (PPG), entitled, "Signal Transduction and Alzheimer's Disease". This PPG was developed from a program established in the Laboratory of Molecular and Cellular Neuroscience in 1990 for the purpose of investigating the biochemistry, cell biology, molecular biology, and pharmacology of regulation, by protein phosphorylation, of the Alzheimer amyloid precursor protein (APP). A group of experts in various disciplines of biomedical research will carry out these studies using distinct but complementary approaches. The Project, entitled "APP binding proteins, APP phosphorylation and regulation of Cdk5", will examine the interaction between APP and FE65 in neurons, the phosphorylation of APP by Cdk5 in neurons, and the regulation of Cdk5. The Project, entitled "Cellular mechanisms for hormonal regulation of BetaAPP trafficking and ABeta generation", will utilize cell-free systems to advance our understanding of how gonadal hormones and insulin modulate the composition and trafficking of vesicular organelles. The Project, entitled "Signal transduction pathways by which gonadal hormones and insulin regulate intracellular and extracellular levels of ABeta in vitro and in vivo", will identify the receptors and intracellular messengers involved in the signal transduction pathways which modulate the changes in ABeta metabolism caused by gonadal hormones and insulin. These studies will be supported by a Scientific Core that will produce key materials and perform routine, yet critical, tasks that will be required to accomplish the studies described in the other Projects. An Administrative Core will coordinate various aspects of the PPG, integrating day-to-day activities of the investigators and consultants involved in the various projects.